Tacrolimus pharmacokinetics and pharmacogenetics: influence of adenosine triphosphate‐binding cassette B1 (ABCB1) and cytochrome (CYP) 3A polymorphisms

Abstract

Tacrolimus, an immunosuppressant used after organ transplantation, has a narrow therapeutic range and its pharmacokinetic variability complicates its daily dose assessment. P-glycoprotein (P-gp), encoded by the adenosine triphosphate-binding cassette B1 (ABCB1) and the cytochrome (CYP) 3A4 and 3A5 enzymes appears to play a role in the tacrolimus metabolism. In the present study, two different renal transplant recipient groups were used to examine the influence of ABCB1 and CYP3A polymorphisms on the daily tacrolimus dose and several pharmacokinetic parameters. In total 63 Caucasian renal transplant recipients divided into 26 early [median (range) of the days since transplantation - 16 (3-74)] and 37 late [median (range) of the days since transplantation - 1465 (453-4128)] post-transplant recipients were genotyped for ABCB1 and CYP3A polymorphisms. The pharmacokinetic parameters of tacrolimus were determined for all renal transplant recipients and correlated with their corresponding genotypes. A significant difference in allele frequencies of the CYP3A4*1B (P = 0.028) and CYP3A5*1 (P = 0.022) alleles was observed between the early and late post-transplant recipient groups. Significantly higher dose-normalized trough levels (dnC(0)), dose-normalized area under the curve (dnAUC(0-12)), and dose-normalized maximum concentration (dnC(max)) were observed for carriers of the CYP3A5*3 variant allele in both renal transplant patient groups. Except for the daily tacrolimus dose (P = 0.025) no significant differences were observed for carriers of the CYP3A4*1B variant allele. Neither the individual ABCB1 polymorphisms nor the ABCB1 haplotypes were associated with any pharmacokinetic parameter. We noticed that patients carrying a CYP3A5*1 allele require a twofold higher tacrolimus dose compared with homozygous carriers of the CYP3A5*3 variant allele to maintain the target dnAUC(0-12). Therefore, genotyping for the CYP3A5*3 variant allele can contribute to a better and more individualized immunosuppressive therapy in transplant patients.

Conversion from twice daily tacrolimus capsules to once daily extended‐release tacrolimus (LCP‐Tacro): Phase 2 trial of stable liver transplant recipients

“…It is well documented that, largely because of a high frequency of the CYP3A5 genetic polymorphism (which acts to increase the clearance and lower the oral bioavailability of tacrolimus), blacks require higher tacrolimus drug doses to achieve the same drug level achieved by nonblacks. [20][21][22][23][24][25][26] Specifically, the wild-type gene CYP3A5*1, which allows significant production of cytochrome P450 3A5, is reportedly absent in 60% to 90% of nonblacks and yet is present in 55% of blacks. This may partially account for lower tacrolimus troughs and higher tacrolimus dose requirements among blacks.…”

Pharmacogenetics and Renal Transplantation

“…However, in another study of 63 Caucasian renal transplant recipients with a complete 9-point 12-hour AUC of Tac, 3 SNPs in the ABCB1 system were genotyped. Neither the individual ABCB1 polymorphisms nor the ABCB1 haplotypes were associated with any pharmacokinetic parameter (Op den Buijsch et al, 2007). On the other hand, in a study of Chinese renal transplant recipients (Cheung et al, 2006), individuals carrying the 2677TT or 3435TT genotype has a significantly lower dose-normalized AUC 0-12 , but no correlation was found between ABCB1 system haplotype and dose-normalized AUC 0-12 .…”

“…In fact, the CYP3A5*3 polymorphism may explain 35.3% of the variation in the daily Tac dose observed in the renal transplant recipients. In another study involving Caucasian population (Op den Buijsch et al, 2007), significantly higher dose-normalized C 0 , dose-normalized AUC 0-12 and dose-normalized peak concentrations (C max ) is demonstrated in carriers of the CYP3A5*3 allele in both early and late post renal transplant recipient groups than in patients homozygous for CYP3A5*1. In their centre, a complete Tac pharmacokinetic profile was usually requested early for patients who failed to achieve the target Tac concentration shortly after transplantation.…”

Calcineurin Inhibitor-Induced Renal Allograft Nephrotoxicity

“…Despite of limitations associated with low population CYP3A4*1B allele frequency, lower C 0 concentrations of tacrolimus were demonstrated in its carriers in 3 rd and 12 th month after transplantation, compared to CYP3A4*1 homozygotes 94 . Patients with CYP3A5*3 polymorphism and missing enzyme activity exhibited higher blood levels and required lower maintenance doses of tacrolimus compared to the CYP3A5*1 variant 95,96,90,97 . For MDR1 and tacrolimus pharmacokinetics, carriers of 2677T or 3435T alleles were found to have higher average levels of tacrolimus compared to 2677 G homozygotes (GG) and 3435 C homozygotes (CC) 98,99 .…”